CN103275091A

CN103275091A - Ixabepilone total synthesis

Info

Publication number: CN103275091A
Application number: CN2013101271985A
Authority: CN
Inventors: 王达桂; 张小勇; 田小艳; 阎家麒
Original assignee: SHENZHEN JIATAI PHARMACEUTICAL Co Ltd
Current assignee: SHENZHEN JIATAI PHARMACEUTICAL Co Ltd
Priority date: 2013-04-15
Filing date: 2013-04-15
Publication date: 2013-09-04

Abstract

The invention belongs to the technical field of drug synthesis and relates to an intermediate of ixabepilone, an ixabepilone total synthesis method and an ixabepilone use. Ixabepilone has a structural formula 1 shown in the patent specification.

Description

Ipsapirone is complete synthesis

Technical field

The present invention relates to a kind of preparation method of cancer therapy drug, specifically the total synthesis method of the lactam derivatives ipsapirone of a kind of epothilone B (Epothilone B).

Background technology

Ipsapirone (ixabepilone, BMS-247550, the injection trade(brand)name: Ixempra) be a kind of be raw material with the epothilone B, adopt the derivative of the epothilone B of semisynthesis preparation, by impelling the stable antitumor action of bringing into play of tumour cell microtubule, tumour cell to the pharmacological agent of multiple anti-Japanese yew class is effective, comprises the cell of those overexpression multidrug resistance gene (MDR) and the cell of generation 'beta '-tubulin transgenation.Studies show that the epothilone B derivative has good action to Japanese yew class resistance, recurrence and insensitive tumour.U.S. FDA is in the listing of approval on October 16th, 2007 this product, and list is used or share treatment transitivity or the local advanced breast cancer invalid to other chemotherapeutics with capecitabine.

The chemistry of ipsapirone is called (1S, 3S, 7S, 10R, 11S, 12S, 16R)-7,11 dihydroxyl-8,8,10,12,16-pentamethyl--3-[(1E)-1-methyl isophthalic acid 2-(2-methyl-4-thiazolyl) vinyl]-17-oxa--4-azabicyclo [14.1,0] heptadecane-5, the 9-diketone, its structural formula is as follows:

At present, except ipsapirone had gone on the market, all the other several ebormycine homologues had entered the clinical study stage, comprised " first-generation ebormycine " (natural product)---epothilone B; The husky dagger-axe of " s-generation ebormycine " (semi-synthetic derivative)---the amino epothilone B of ebormycine D, 21-and KOS-1584 and " third generation ebormycine " (complete synthesis derivative)---grand (sagopilone) and ABJ879.

Ebormycine (Epothilones) is the secondary metabolite that is produced by glutinous bacterial fibers heap capsule bacterium Sorangium cellulosum, and its structure is body centered by 16 yuan of big rings of lactone, and the thiazole ring aglucon is a class cytotoxic compound of side chain.Glutinous bacterial fibers heap capsule bacterium is the microbiologist of German GBF in 1985

Deng what in the earth on Zambesi riverbank, South Africa, find.

The speed of growth of slime bacteria sorangium cellulosum is very slow, and its doubling time is 16h, and the original strain fermentation production rate of epothilone B only is 0.12～0.5mgL ^-1At present, we have adopted physics, chemistry and the seed selection of gene reorganization method superior strain has improved the productive rate of ebormycine, makes epothilone B shake flask fermentation productive rate reach 80mgL ^-1About.But when being amplified to tonne fermentor tank and carrying out industrial fermentation, its productive rate still can not be stabilized in 30mgL ^-1More than.Because the genetic background of slime bacteria sorangium cellulosum is very fuzzy, the transformation efficiency of the foreign DNA of the glutinous bacterium of this kind is low, the restriction of available biology tool in addition, this bacterium is carried out quite difficulty of dna molecular transformation, be difficult to cultivate the high yield engineering bacteria of epothilone B, thereby restricted the suitability for industrialized production of epothilone B.Semi-synthetic ipsapirone is condition to have enough epothilone B products, does not have the epothilone B of q.s as raw material, and semi-synthetic ipsapirone just can not be accomplished scale production.

At present, BMS is to be raw material with the epothilone B, and semi-synthetic ipsapirone (US6605599, WO9902514).Though the semisynthesis route is simple, productive rate is very low, has only 18～20%, and its actual yield is 10～15% only, causes the ipsapirone production cost very high.

The route of the semi-synthetic ipsapirone of BMS is as follows:

Ipsapirone can pass through semi-synthetic the getting of epothilone B (I), namely the open loop through lactone under the catalysis of palladium catalyst (stablizing allyl cation) obtains nitrine carboxylic acid (II) with sodiumazide or TBuA trinitride, obtain amino acid (III) in trimethyl-phosphine (or triphenylphosphine or Pd/C catalytic hydrogenation) reduction, and then obtain target compound through DPPA or EDC/HOBT dehydrating condensation.BMS company is that the three-step reaction that raw material only is converted to an atom C N has just obtained target product with the epothilone B, has limited its application but its initial feed is baroque natural product.

The advantage of the complete synthesis ipsapirone of the present invention is to abandon loaded down with trivial details difficult fermentation process, need not to build huge fermentation plant and complicated auxiliary facility, has saved facility investment and production cycle greatly.Complete synthesis ipsapirone is not subjected to device-restrictive, and preparative-scale amplifies easily, the more important thing is that production cost is low, and is with short production cycle.

The complete synthesis ipsapirone method that the present invention relates to is the bigger technology of difficulty in the organic synthesis field.Relevant report was done by external Danishefsky group, as J.Org.Chem., and 2011,66:4369-4378; Organic Letters.2000,2:1637-1639, they adopted a large amount of no commercially available, need homemade chiral reagent and catalyzer, reaction conditions is extremely harsh, synthetic overall yield less than 0.23%.Therefore, this method has only the laboratory meaning, the hopeless industrial-scale production ipsapirone that is applied to.

The complete synthesis strategy of ipsapirone of the present invention

The structure of the structure Aza-dEpoB of ipsapirone (aza-EpoB) is close, has therefore drawn the complete synthesis key structure fragment of ipsapirone on the complete synthesis basis of research Aza-dEpoB.Synthetic route contrast with Aza-dEpoB; though the framework construction of moieties Segment A is a new route; but acyl group structure fragment B can obtain in the dEpoB of Danishefsky research team is synthetic, and only being connected of two critical segment A and B need coupling realize through B-alkyl Suzuki under the catalysis of palladium.The asymmetric hydrogenation of ruthenium catalyst can obtain highly selective C-3 chiral structure, and amino and the carboxyl of sloughing protecting group obtain Macrocyclic lactams aza-dEpoB through dehydrating condensation, carry out epoxidation then and obtain target product.As seen, utilize existing synthetic method can synthesize the Macrocyclic lactams ipsapirone efficiently through simple transformation.

Summary of the invention

Therefore, the present invention relates to C4-(demethylation or two falling)-ipsapirone and salt thereof of formula I,

Wherein:

R ₁Expression NH,

R2 be hydrogen do not replace or by hydroxyl, low-grade acyloxy, be the amino low alkyl group that replaces of low-grade alkane acidyl, lower alkoxy, halogen, amino, low-grade alkyl amino, two-low-grade alkyl amino or lower acyl free or the protection form,

R3 is the heteroaryl that does not replace or replace with at least one nitrogen-atoms,

R4 represents hydrogen or low alkyl group, preferable methyl,

R6 is hydrogen, and

R7 is hydrogen or low alkyl group,

Z is O,

Condition is:

When R3 is 2-methyl-thiazolyl and Z when being O, R2 represent not replace or by the amino low alkyl group that replaces of hydroxyl, low-grade acyloxy, lower alkoxy, halogen, amino, low-grade alkyl amino, two-low-grade alkyl amino or lower acyl and

When R3 is 2-methyl-thiazolyl and Z when being key, R2 represents by the amino low alkyl group that replaces of hydroxyl, low-grade acyloxy, lower alkoxy, halogen, amino, low-grade alkyl amino, two-low-grade alkyl amino or lower acyl.

Except as otherwise noted, otherwise before this and the generic term of hereinafter using preferably in context of the present disclosure, have following meanings:

Wherein think for the plural form of compound, salt etc. and also refer to simplification compound, salt etc.

Any unsymmetrical carbon all can with (R)-, (S)-or (R, S)-configuration exists, preferably exist with (R)-or (S)-configuration.Therefore described compound can exist with mixture of isomers or pure isomer, preferably the diastereomer with enantiomer-pure exists.

Formula I represents two kinds of steric isomers.The present invention relates to two kinds of steric isomers, preferred formula Ia compound by formula Ia and the two expression of Ib,

Wherein each symbol and group have as above to the given implication of formula I compound.

Prefix " rudimentary " expression has being no more than and comprises 7, especially is no more than and comprises that the group of 4 carbon atoms, wherein said group are straight chain group or for having the branched group of one or more branches.

" halogen " is fluorine, chlorine, bromine or iodine.

" alkyl " be low alkyl group preferably.

" low alkyl group " is straight or branched; For example it is butyl such as normal-butyl, sec-butyl, isobutyl-, the tertiary butyl; Propyl group such as n-propyl or sec.-propyl; Ethyl or methyl.Preferred low alkyl group is methyl, ethyl, n-propyl, sec.-propyl or the tertiary butyl.

" alkoxyl group " be lower alkoxy preferably, for example methoxyl group, oxyethyl group, isopropoxy or uncle's fourth oxygen.

" acyl group " be lower acyl, for example ethanoyl preferably.

" low-level chain triacontanol " be methyl alcohol, ethanol, 1-propyl alcohol, 2-propyl alcohol, 1-butanols or 2-butanols preferably.

" lower alkane " be pentane, hexane or heptane especially.

" heteroaryl " expression with at least one nitrogen-atoms contains the list of at least 1,2 or 3 theheterocyclic nitrogen atom and 0 or 1 Sauerstoffatom and 0 or 1 sulphur atom-or bicyclic radicals, this group will be undersaturated in this heteroaryl and the ring that the rest part of formula 1 molecule is connected, and preferably wherein shack preferably have 5-12, the more preferably group of 5 or 6 annular atomses; And described heteroaryl can not replace or by one or more, especially 1 or 2 be preferably selected from the substituting group of halogen, alkoxyl group, alkylthio, hydroxyl, alkyloyl or most preferably replaced by alkyl.Preferred described list-or bicyclic heteroaryl be selected from: the 2H-pyrryl, pyrryl, imidazolyl, benzimidazolyl-, pyrazolyl, indazolyl, purine radicals, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, the 4H-quinolizinyl, isoquinolyl, quinolyl, 2, the 3-phthalazinyl, the naphthyridine base, quinoxalinyl, quinazolyl, quinnolinyl, pteridyl, the 3H-indyl, indyl, pseudoindoyl oxazolyl isoxazolyl, thiazolyl, isothiazolyl, benzo [b] thiazolyl, triazolyl, tetrazyl, benzo [b] oxazolyl and benzo [d] pyrazolyl.

In the presence of electronegative group such as carboxyl or sulfo group, also can form salt with alkali, for example metal-salt or ammonium salt, as basic metal or alkaline earth salt, for example sodium, potassium, magnesium or calcium salt, the perhaps ammonium salt that forms with ammonia or suitable organic amine is as monobasic tertiary amine, for example triethylamine or three (2-hydroxyethyl) amine or heterocyclic bases, for example N-ethyl-piperidines or N, N '-lupetazin.

In the time of in basic group and acidic-group are present in a part, formula I compound also can form inner salt.

Consider the substantial connection between the new compound of the salt form (comprise and can be used as those salt of for example purifying or identifying the intermediate of described new compound) that is free form and is them, before this and hereinafter, allly all be interpreted as also referring to corresponding salt when mentioning free cpds, if suitable and favourable.

The ipsapirone of formula Ia or Ib or its salt,

Wherein:

R1 represents NH,

R4 represents hydrogen or low alkyl group,

R6 is hydrogen, and

R7 is hydrogen,

Z is O,

Condition is:

When R3 is 2-methyl-thiazolyl and Z when being O, R2 represents not replace or by the amino low alkyl group that replaces of hydroxyl, low-grade acyloxy, lower alkoxy, halogen, amino, low-grade alkyl amino, two-low-grade alkyl amino or lower acyl, and

The ipsapirone of formula Ia or Ib or its salt, wherein:

R1 represents NH,

Be hydrogen do not replace or by hydroxyl, low-grade acyloxy, be the amino low alkyl group that replaces of low-grade alkane acidyl, lower alkoxy, halogen, amino, low-grade alkyl amino, two-low-grade alkyl amino or lower acyl free or the protection form,

R3 is thiazolyl, oxazolyl, pyridyl, benzothiazolyl, benzoxazolyl or benzimidazolyl-, and they do not replace separately or are substituted,

R4 represents hydrogen or low alkyl group,

R6 is hydrogen, and

R7 is hydrogen,

Z is O,

Condition is:

The method of the ipsapirone of formula I,

Wherein:

R1 represents NH,

R2 is hydrogen or do not replace or by the amino low alkyl group that replaces of hydroxyl, low-grade acyloxy, lower alkoxy, halogen, amino, low-grade alkyl amino, two-low-grade alkyl amino or lower acyl,

R4 represents hydrogen or low alkyl group,

R6 is hydrogen, and

R7 is hydrogen,

Z is O,

Wherein in the first step, use the formula II,

Wherein R1, R2 have as above the given implication of formula I compound, and R3 is halogen, and R4 is alkyl, with the olefine reaction of formula III,

Wherein R1, R2 and R3 are similar and different protecting groups.

Obtain the aldol of formula IV,

Wherein R1, R2, R3 and Z have as above the given implication of formula I compound, and R4 is protecting group, R5 be H or with the similar and different protecting group of R4, and R6 is hydrogen,

In second step, the aldol that makes formula IV with can introduce and the reagent react of the protecting group that R4 is similar and different, obtain the carboxylic acid of formula IV; wherein R1, R2, R3 and Z have as above to the given implication of formula I compound; R4 is protecting group, and R5 is that H or R5 and R6 are the protecting groups similar and different with R4

In the 3rd step, the carboxylic acid that makes formula IV with can not cause removing the reagent react of removing protecting group R4 under the condition of protecting group R5 and R6, obtain the carboxylic acid of formula IV; wherein R1, R2, R3 and Z have as above to the given implication of formula Iization platform thing; R4 is hydrogen, and R5 is that H or R5 and R6 are protecting groups

In the 4th step, the carboxylic acid of formula IV is carried out the macrolide reaction, obtain the esperamicin of formula I, wherein R1, R2, R3 and Z have as above the given implication of formula I compound, and R1 is NH, and R5 is that H or R5 and R6 are protecting groups.

In the 5th step; make the ipsapirone and the reagent react that can remove protecting group R5 and R6 of formula I; obtain the ipsapirone of formula I; wherein R1, R2, R3, R5, R6 and Z have as above to the given implication of formula I compound; and R1 is NH, and with the optional ipsapirone that further transforms accepted way of doing sth I of the ipsapirone of this formula I, wherein R1, R2, R3, R5, R6 and Z have as above to the given implication of formula I compound; and R1 is NH, and wherein R7 is hydrogen or low alkyl group.

Description of drawings

Fig. 1 is the chemical structure of ebormycine three generations derivative.

Embodiment

Further specify the present invention with specific embodiment below, but these embodiment only tool is exemplary, be not the restriction to technical solution of the present invention.

Synthesizing of embodiment 1 fragment 1

The synthetic route of fragment 1

Ipsapirone fragment 1 synthetic route

The preparation of compound (2)

Under 0 ℃, to oxysuccinic acid (in the suspension of L-(-)-malic acid5.0g (37.3mmol) and dry ether 100ml, drip hexanaphthene 3.9ml (37.3mmol) and the boron trifluoride ethyl ether complex 6.7ml (54.1mmol) of new distillation with syringe, suspension transfers clear solution gradually to, and mixed solution stirs 1h down at 0 ℃.Remove ice bath then, mixed solution at room temperature stirs and spends the night.Reaction mixture is with ether 200ml dilution, with (3 * 40ml) washings of 10% aqueous sodium acetate solution.The water extracted with diethyl ether that merges, the organic phase of merging is passed through anhydrous sodium sulfate drying with saturated brine 20ml washing 1 time.Vacuum concentration gets crude acid 2, and a kind of dense yellow oil leaves standstill solidifiable.Recrystallization (ether-normal hexane) obtains 28.0g (100%), is a kind of canescence crystallization.

mp104-105℃.

¹H?NMR(300MHz，CDCl3)：δ11.48(bs，1H，CO2H)，4.71(dd，J ₁＝3.98，J ₂＝6.48，1H，OCHCO ₂)，2.90(d?of?AB，J＝3.98，6.48，J _AB＝17.21，2H，CH2-CO2)；1.60-1.89(m，?8H，cyclic

)，1.30-1.58(m，2H，cyclic?CH2；

¹³C?NMR(75MHz，CDCl3)：δ174.97，171.82，112.04，69.87，36.07.36.02，35.14，24.23，22.82，22.75.IR(CCl4)：3450，2940，1780，1720，1370，1280，1220，1150，1110，940cm ^-1.

MS(high?resolution)：m/z?M ⁺(C ₁₀H ₁₄O ₅)，calcd214.0841，found214.0835.Anal.Calcd?for?C ₁₀H ₁₄O ₅：C，56.07；H，6.59.Found：C，56.29；H.6.72.

The preparation of compound (3)

Borine methyl thioether complex compound 100ml (200mmol, 2.0M) and trimethyl borate 24.2ml (200mmol) be dissolved in the mixed solution of THF175ml, be cooled to 0 ℃, drip the solution that 215.04g (70.2mmol) is dissolved in THF70ml.Reaction mixture at room temperature stirs 24h, is cooled to 0 ℃, drips methyl alcohol 70ml, and mixed solution at room temperature stirs 1h.Decompression steams solvent, obtains a kind of dense thick oily matter.This operation repeats 2 times with methyl alcohol 105ml, obtains a kind of water white oil.Crude product is a kind of 3 and (5S)-(1 '-hydroxyethyl)-2,2-cyclohexylidene-1, the mixture of 3-dioxolan-4-one, it is dissolved in methylene dichloride 175ml, add tosic acid-hydrate 1.335g (7.02mmol, 0.1equiv), mixed solution at room temperature stirs 24h, adds triethylamine 0.98ml.The mixed solution concentrating under reduced pressure, residue obtains lactone 35.16g (72%) with flash chromatography (ether) purifying.A kind of water white oil.

[α] ²⁰ _D＝-60.1[α] ²⁰ ₅₄₆＝-71.3(c＝0.67，CHCL ₃).

IR(film)：v ^～ _max＝3400，1773，1378，1221，1185，1128，1015，947，719cm ^-1；

¹H?NMR(400MHz，CDCl ₃)：δ＝4.54(t， ³J＝9.2Hz，1H；H-3)，4.43(td，? ³J＝9.0Hz， ³J＝2.1Hz，1H；H-5)，4.29±4.22(m，1H；H-5)，3.90(s，1H，OH).2.66±2.58(m，1H；H-4)，2.35±2.26(m，1H；H-4)；

¹³C?NMR(100MHz，CDCl3)：δ＝178.2，67.4，65.2，30.8；

MS(PCI，CH4)：m/z(％)：116.9(6)[M+CH4] ⁺，102.9(100)[M] ⁺，84.9(3)

The preparation of compound (4)

Imidazoles 241mg (3.54mmol, 2.2equiv) and TERT-BUTYL DIMETHYL CHLORO SILANE 267mg be dissolved in (1.77mmol 1.1equiv) adds lactone 3164mg1.61mmol) solution of dimethyl formamide 1.5ml.Mixed solution stirs 24h under room temperature, reaction mixture obtains silicon ether 4321mg (93%), a kind of water white oil through flash chromatography (Skellysolve A/ether 10: 1) purifying.

[α] ²⁰ _D＝-31.7[α] ²⁰ ₅₄₆＝-37.4(c＝0.86，CHCL ₃)；

IR(film)：v ^～ _max＝2931，2859，1790，1473，1362，1254，1154，1022，840.781cm ^-1；

¹H?NMR(400MHz，CDCl3)：δ＝4.43±4.35(m，2H；H-5，H-3)，4.22±4.15(m，1H：H-5)，2.49±2.41(m，1H；H-4)，2.27±2.21(m，1H；H-4)，0.91(s，9H，OSiC(CH3)3)，0.17，0.14(2s，2×3H；OSi(CH3)2)；

¹³C?NMR(100MHz，CDCl3)：δ＝175.8，68.2，64.7，32.3，25.6，18.2，-4.8，-5.3；

MS(70eV，EI)：m/z(％)：217.1(20)[M+H] ⁺，201.0(81)[M-CH3] ⁺，189.0(6)，171.0(78)，159.2(79)[M-tBu] ⁺，146.8(13)，145.0(16)，130.9(100)，114.9(92)，102.9(35)，100.9(37)；

HRMS(EI)：calcd?for?C6H11O3Si[M-tBu] ⁺159.0477，found159.047.

The preparation of compound (5)

Lithium methide 1.65M diethyl ether solution 0.67ml (1.11mmol, 1.1equiv) stir and to splash into 4 218mg (1.01mmol) that are cooled to-78 ℃ down and be dissolved in the THF4ml solution, after stirring 3h under-78 ℃, with glacial acetic acid 72 μ l (1.26mmol, 1.25equiv) stopped reaction, add ether 20ml and saturated sodium bicarbonate solution aqueous solution 10ml, tell organic layer after stirring 5min, (2 * 20ml) extract water layer with ether, the organic extract liquid anhydrous magnesium sulfate drying that merges, concentrating under reduced pressure, obtain crude product (3S)-3-[(tert-Triethylsilyl)-2-methyl-tetrahydrofuran-2-ol235mg (93%), a kind of colorless solid crystallization (mixture of diastereomer), need not purifying, for the synthesis of ketone 5: imidazoles 125mg (1.84mmol, 2.2equiv) and TESCl139mg (0.92mmol, 1.1equiv) add to (3S)-3-[(tert-Triethylsilyl)-2-methyl-tetrahydrofuran-2-ol194mg (0.83mmol) and be dissolved in the solution of DMF0.8ml, mixture at room temperature stirs 24h, reaction mixture flash chromatography (pentane/ether 20: 1) purifying, obtain ketone 5 226mg (78%), be a kind of water white oil.

[α] ²⁰ _D＝-8.9(c＝1.0，CHCl ₃)；

IR(film)：v ^～ _max＝2957，2859，1720，1473，1361，1256，1106，838，778cm ^-1：

¹H?NMR(400MHz，CDCl3)：δ＝4.15(dd， ³J＝6.8Hz， ³J＝5.3Hz，1H；H-3)，3.75±3.58(m，2H；H-5)，2.16(s，3H；H-1)，1.88±1.70(m，2H；H-4)，0.92，0.88(2s，2×9H；OSiC(CH3)3)，0.06，0.06，0.04，0.03(4s，4×3H；OSi(CH3)2)；

¹³C?NMR(100MHz，CDCl3)：δ＝212.0，75.8，58.4，37.8，25.9，25.7，25.4，18.3，18.1，-5.0，-5.1，-5.4；

MS(PCI，NH3)：m/z(％)：347(100)[M+H] ⁺.，324(17)，279(93)，231(4)，215(7)，157(8)，94(11)；

HRMS(EI)：calcd?for?C ₁₇H ₃₈O ₃Si ₂346.2360，found346.235

The preparation of compound (7)

N-Butyl Lithium 23.5ml (58.7mmol, the 2.5M hexane solution of 1.2equiv) is splashed into 6 14.64g that stirring that are cooled to-78 ℃, and (58.7mmol 1.2equiv) is dissolved in the solution of THF150ml.Mixed solution is after-78 ℃ are down stirred 1h, and (48.9mmol 1.0equiv) is dissolved in the solution of THF100ml to drip methyl ketone 5 16.96g down at-78 ℃.Mixed solution rises to room temperature in 12h.With saturated ammonium chloride (NH ₄Cl) aqueous solution 100ml stopped reaction.Tell organic layer, (3 * 100ml) extractions, the organic extract of merging is by anhydrous magnesium sulfate drying, concentrating under reduced pressure with ether for water layer.Flash chromatography (methylene dichloride, ether then) purifying obtains methyl ketone 5 3.2g that do not transformed, 22%) and E olefin (alkene) 7 12.07g (79%), a kind of water white oil.

[α] ²⁰ _D＝-0.7(c＝0.46，CH ₂Cl ₂)；

IR(film)：v ^～ _max＝2956，2858，1472，1256，1099，836，776cm ^-1；

¹H?NMR(400MHz，CDC13)：δ＝6.91(s，1H；H-5′)，6.47(s，1H；H-5)，4.31(dd，? ³J＝8.0Hz， ³J＝4.6Hz，1H；H-3)，3.71±3.58(m，2H；H-1)，2.70(s，3H；C2′-CH3)，1.99(d，? ⁴J＝1.1Hz，3H；C4-CH3)，1.83±1.75(m，2H；H-2)，0.89，0.88(2s，2×9H；OSiC(CH3)3)，0.06，0.00(2s，2×3H；OSi(CH3)2)，0.03(s，6H；OSi(CH3)2)；

¹³C?NMR(100MHz，CDCl3)：δ＝164.3，153.2，142.6，118.6，115.0，75.0，59.6，39.8，25.9，25.8，19.2，18.2，13.8，-4.6，-5.1，-5.3，-5.4；

MS(70eV，EI)：m/z(％)：441.2(35)[M] ⁺，384.1(89)[M-tBu]+，356.1(80)，309.1(49)，282.1(65)[C ₁₄H ₂₄NOSSi] ⁺，252.0(70)，178.0(38)，147.0(71)，73.1(100)；

HRMS(EI)：calcd?for?C ₂₂H ₄₃NO2SSi ₂441.2553，found441.255.

The preparation of compound (8)

7 13.255g (30.0mmol) are dissolved in the mixed solution of a kind of ether 120ml and acetonitrile 120ml, with 40% aqueous solution 20ml of hydrofluoric acid and the glass fragment 133mg of fine grinding, add in the mixed solution of vigorous stirring under 0 ℃.Under 0 ℃, mixed solution stirs 2h, adds hydrofluoric acid 20ml again, continues to stir 1h down at 0 ℃.Under 0 ℃, carefully add stopped reaction in solid sodium bicarbonate 84.0g (1.0mo1) 15min.Mixed solution adds water, until solid dissolving (if desired, can further add sodium bicarbonate makes the pH value transfer to 6～8) after 0 ℃ is stirred 30min down.(anhydrous magnesium sulfate drying is passed through in 4 * 200m1) extractions, the organic extract liquid of merging saturated brine 100ml washing to mixed solution with methylene dichloride, concentrating under reduced pressure, residue flash chromatography (pentane/ether, 4: 1) purifying, obtain pure 8 9.041g (92%), a kind of water white oil of thickness.

[α] ²⁰ _D＝-5.7(c＝1.0，CHCl ₃)；

IR(film)：v ^～ _max＝3357，2955，2857，1472，1252，1074，837，777cm ^-1；

¹H?NMR(400MHz，CDCl3)：δ＝6.92(s，1H；H-5′)，6.52(s，1H；H-5)，4.38(dd，? ³J＝7.4Hz， ³J＝4.5Hz，1H；H-3)，3.80±3.67(m，2H；H-1)，2.70(s，3H；C2′-CH3)，2.40(s，1H；?OH)，2.01(d， ⁴J＝1.2Hz，3H；C4-CH3)，1.93±1.76(m，2H；H-2)，0.91(s，9H；OSiC(CH3)3)，0.10，0.03(2s，2×3H；OSi(CH3)2)；

¹³C?NMR(100MHz，CDCl3)：δ＝164.5，153.0，141.6，118.8，115.4，77.5，60.4，38.2，25.8，19.2，18.1，14.4，-4.6，-5.2；

MS(70eV，EI)：m/z(％)：327(18)[M] ⁺，282(39)，270(94)[M-tBu]，268(29)，252(12)，240(14)，178(41)，168(100)，164(23)，105(27)，75(59)，73(42)；

HRMS(EI)：calcd?for?C ₁₆H ₂₉NO ₂SSi327.1688，found327.168.

The preparation of compound (9)

Dimethyl sulfoxide (DMSO) 2.04ml (28.8mmol, 2.4equiv) be dissolved in methylene dichloride 6ml, under-78 ℃, in 5min, drop to the oxalyl chloride 1.14ml that stirring (13.2mmol 1.1equiv) is dissolved in the solution of methylene dichloride 30ml, mixed solution under-70 ℃ under-70 ℃.Splash into 8 3.93g (12.0mmol) and be dissolved in the solution of methylene dichloride 5ml in 5min, mixed solution stirs 30min down at-70 ℃, drips triethylamine 84ml (60mmol) stopped reaction.Reaction mixture rises to room temperature in 45min, add water 30ml, mixed solution stirs 10min, tells organic layer, water layer dichloromethane extraction (3 * 100ml), the organic extract liquid that merges passes through anhydrous magnesium sulfate drying, concentrating under reduced pressure, flash chromatography (pentane/ether, 5: 2) purifying, obtain aldehyde 9 3.21g (82%), a kind of light yellow oil.

[α] ²⁰ _D＝-19.2[α] ²⁰ ₅₄₆＝-22.1(c＝1.0，CHCl ₃)；

IR(film)：v ^～ _max＝2956，2857，1727，1472，1389，1254，1085，838，778cm ^-1；

¹H?NMR(400MHz，CDCl3)：δ＝9.79(t，3J2.7Hz，1H；H-1)，6.94(s，1H；H-5′)。6.56(s，1H；H-5)，4.69(dd， ³J＝8.2Hz， ³J＝^4.0Hz，1H；H-3)，2.75(ddd， ²J＝^15.5Hz， ³J＝^7.7Hz， ³J^＝2.9Hz，1H；H-2)，2.70(s，3H；C2′-CH3)，2.51(ddd， ²J^＝15.5Hz， ³J^＝4.0Hz， ³J＝^2.1Hz，1H；H-2)，2.04(d， ⁴J＝1.2Hz，3H；C4-CH3)，0.88(s，9H；OSiC(CH3)3)，0.08，0.03(2s，2×3H；OSi(CH3)2)；

¹³C?NMR(100MHz，CDCl3)：δ＝201.5，164.8，152.6，140.5，119.3，115.9，73.9，50.1，25.7，19.2，18.1，14.1，-4.6，-5.2；

MS(70eV，EI)：m/z(％)：325(6)

282(24)，268(98)[M-tBu] ⁺，250(17)，194(13)，176(100)，164(19)，135(15)，101(20)，75(32)，73(31)；

HRMS(EI)：calcd?for?C ₁₆H ₂₇NO ₂SSi325.1532，found325.153.

The preparation of compound (10)

N-Butyl Lithium 5.14g (12.86mmol, 1.96equiv) the 2.5M pentane solution, add the ethyltriphenylphosphiodide iodide phosphine 13.12mmol that is stirring down at 0 ℃, 2.0equiv be dissolved in the suspension of THF60ml, the red phosphine inner salt drips of solution that gained is limpid adds to the quick iodine 3.163g (12.46mmol that is stirring, 1.90equiv) be dissolved in the solution of THF90ml, be cooled to-78 ℃.The yellow suspension of gained at-78 ℃ of following vigorous stirring 10min, is stirred 30min at-30 ℃ to-40 ℃.Under-30 ℃, and two (trimethyl silicon based) ammonification sodium 1.0M THF solution 11.81ml of dropping in 10min (11.81mmol, 1.8equiv).Mixed solution stirs 15min down at-30 ℃, drips the solution that aldehyde 9 2.137g (6.65mmol) are dissolved in THF30ml in 10min.Mixed solution stirs 10min under-30 ℃, with saturated aqueous ammonium chloride 10ml stopped reaction.Add pentane 150ml, mixed solution filters by a small amount of silica filler, with pentane/ether, and 4: 1,400ml wash-out pillar, filtrate decompression concentrates, residue flash chromatography (pentane/ether, 10: 1) purifying, obtain vinyl iodide 10 1.64g (54%), a kind of light yellow oil.

[α] ²⁰ _D＝+14.2[α] ²⁰ ₅₄₆＝+18.5(c＝1.0，CHCl ₃)；[α] ²⁰ _D+14.2；

IR(film)：v ^～ _max＝2955，2857，1652，1507，1472，1252，1184，1067，837，777cm ^-1；

¹H?NMR(400MHz，CDCl3)：δ＝6.91(s，1H；H-5")，6.49(s，1H；H-2′)，5.46(td，? ³J＝6.7Hz， ⁴J＝^1.5Hz，1H；H-3)，4.21(t， ³J＝^6.3Hz，1H；H-1)，2.71(s，3H；C2"-CH3)，2.48(d， ⁴J＝^1.4Hz，3H；H-5)，2.44±2.29(m，2H；H-2)，2.02(d， ⁴J^＝1.1Hz，3H；C1′-CH3)，0.90(s，9H，OSiC(CH3)3)，0.06，0.02(2s，2×3H；OSi(CH3)2)；

[0110] ¹³C?NMR(100MHz，CDC13)：δ＝164.4，153.1，141.7，132.1，118.9，115.2，102.3，77.3，43.7，33.7，25.8，19.2，18.2，14.1，-4.7，-5.0；MS(PCI，CH4)：m/z(％)：464.4(100)?

448.3(32)

423.3(3)，406.2(16) 369.2(5)，332.0(50)，282.1(63)，232.3(11)，229.1(23)，205.1(28)；

HRMS(EI)：C ₁₈H ₃₀INOSSi(463.5)：calcd?C46.65，H6.52，N3.02，S6.92；found?C46.67，H6.77，N3.12，S6.57.

The preparation of compound (11)

102.28g (4.92mmol) be dissolved in acetic acid/THF/H ₂O (3: 1: 1) 50ml stirs 8h under room temperature, remove solvent then under reduced pressure, and the oily residue is dissolved in ethyl acetate 100ml, adds among the saturated sodium bicarbonate 50ml and excessive acid.Tell organic layer, water layer ethyl acetate extraction (3 * 50ml), the organic layer that merges use successively saturated sodium bicarbonate (1 * 50ml) and saturated brine (1 * 50ml) washs, use anhydrous magnesium sulfate drying then, solution filters, concentrating under reduced pressure, silica gel chromatography (30% ethyl acetate/hexane) purifying, obtain 111.71g (99%), a kind of yellow oil.

[α] _D+4.9(c1.0，CHCl ₃)；

Rf＝0.19in40％EtOAc/hexanes；

IR(neat)3332，2947，1737，1651，1506，1432，1270，1188，1100，1049，969，881，732cm ^-1；

¹H?NMR(400MHz，CDCl ₃)δ＝7.0(s，1H)，6.58(s，1H)，5.44(t，J＝6.5Hz，1H)，4.28(t，J＝6.4Hz，1H)，2.72(3，3H)，2.44(m，2H)，2.06(s，3H)；

¹³C?NMR(100MHz，CDCl ₃)δ＝164.7，152.4，141.6，131.5，118.9，115.5，103.1，76.1，42.4，33.7，19.0，14.4；

LRMS(+electrospray)：371.9[M+Na] ⁺，349.9[M+H] ⁺

The preparation of compound (12, fragment 1)

111.74g (4.99mmol) be dissolved in toluene 30ml, be cooled to 0 ℃, add diphenyl phosphate azide 1.65g (5.98mmol), add diazabicylo 0.91g (5.98mmol) again.Reaction mixture stirs 2h down at 0 ℃, solution is warming up to 25 ℃ then, adds ethyl acetate 100ml.Organic layer successively water (1 * 30ml), saturated sodium bicarbonate (1 * 50ml) and saturated brine (1 * 50ml) washing by anhydrous magnesium sulfate drying, is filtered, concentrating under reduced pressure, silica gel chromatography (7.5% ethyl acetate/hexane) purifying obtains 121.58g (85%), a kind of light yellow oil.

[α] ²⁰ _D＝-21.3(c＝1.0，CHCl ₃)；

Rf＝0.68in40％EtOAc/hexanes.；

IR(neat)3104，2914，2094，1655，1504，1427，1243，1183，1103，1031，960，877，734cm ^-1；

¹H?NMR(400MHz，CDCl ₃)δ7.01(s，1H)，6.52(s，1H)，5.44(t，J＝6.5Hz，1H)，4.07(t，J＝7.0Hz，1H)，2.70(s，3H)，2.49(s，3H)，2.41(m，2H)，2.10(s，3H)；

¹³C?NMR(100MHz，CDCl ₃)δ164.7，151.8，136.1，130.5，122.2，116.8，103.8，69.5，40.0，33.6，19.2，14.4；

LRMS(+electrospray)：397.1[M+Na] ⁺，375.1[M+H] ⁺，332.0.HRMS?cald?forC ₁₂H ₁₆N ₄SI.375.0142.found375.0139.

The preparation of compound (6)

The mixed solution of 4-chloromethyl-2-methylthiazol hydrochloride 50.0g (340mmol) and triethyl-phosphite 112.5g (677.0mmol) is heated to 160 ℃, stirs 6h.The mixed solution cooling, excessive triethyl-phosphite is removed in underpressure distillation, and residue obtains 672.8g (292.4mmol, 86%), a kind of light yellow oil with fast silica gel chromatogram (5% methanol) purifying.

Rf0.3 (60% ethyl acetate/hexane).

IR(Film)：v ^～ _max＝3455(sbr).2986(s).2927(m).2909(m)，1655(w)；1521(m)，1444(w).1395(w).1323(w)，1244(s).11187(m)，1164(m).1053(vs)，1026(vs)，968(s)cm ^-1；

¹HNMR(400MHz.CDCl ₃，TMS)：δ＝7.06(d， ⁴J(H，＝P)3.9Hz.1H.H-5).4.09(dq，? ³J(H.H)-7.0Hz. ³J(H，P)＝7.8Hz，4H，PO-CH2-CH3).3.35(d， ²J(H.P)＝21.4Hz.2H.P-CH，-).2.69(s.3H，C2-CH3)，1.29(t. ³J(H，H)＝7.0Hz.6H.O-CH，-CH3)；

¹³C?NMR(100MHz，CDCl ₃)：δ＝165.44(s)，145.96(ds，? ²J(C，P)＝8.2Hz).115.67(dd. ³J(C，P)＝7.4Hz)，62.19(dt，2C. ²J(C，P)＝6.4Hz).29.35(dt. ³J(C，P)＝141Hz).19.05(q).16.35(dq，2C， ³J(C.P)＝6.0Hz)；

³¹P?NMR(81MHz.CDCl ₃.H ₃PO，ext.)：δ＝26(s)；

MS(70eV.El)：m/z(％)：＝249(45)[M ⁺].221(6)[M ⁺-C ₂H ₄].204(8)[M ⁺-OEt].176(9).175(10).152(12).140(12).126(23).113(100)[C，H，NS′].112(38)[C ₅H ₇NS ⁺].81(13).71(28).45(15).

Synthesizing of embodiment 2 fragments 2

Fragment 2 synthetic routes

The preparation of compound 13

Under 0 ℃, be dissolved in the interior triethylamine 5.76ml (41.35mmol) of adding of solution of dry acetonitrile 170ml to commercially available 5-benzyloxy Whitfield's ointment 8.6g (41.35mmol), add pivaloyl chloride 5.1ml (41.35mmol) then, add THF35ml to the dense thick white suspension that still can stir.0 ℃ down stir 15min after, add the solution that pseudoephedrine 7.5g (45.5mmol) and triethylamine 6.34ml (45.5mmol) are dissolved in THF120ml fast with sleeve pipe.Reaction mixture stirs 1h down at 0 ℃～5 ℃, is warming up to room temperature in 2h, adds water 50ml stopped reaction then.Removal of solvent under reduced pressure, (3 * 150ml), the organic phase of merging is used 1N aqueous hydrochloric acid 150ml to water successively, saturated sodium bicarbonate aqueous solution 150ml and saturated brine 150ml washing, anhydrous sodium sulfate drying, concentrating under reduced pressure with dichloromethane extraction.The crude product purification by flash chromatography, ethyl acetate: 3: 7～8: 2 gradient elutions of hexane obtain 1312.7g (84%), a kind of dense thick liquid.

[α] ²⁰ _D＝78.98(c＝2.15，CHCl ₃)；

IR(Film，cm ^-1)：3392，2936，2863，1622，1455，1405，1104，1051，737，700.

¹H?NMR(mixture?of?rotamers)：δ0.97and1.1(d，J＝7Hz，3H，N-CH-CH3，rotamers)1.63-1.76(m，4H)，2.23-2.48(m，2H)，2.78and2.91(s，3H，N-Me?rotamers)，3.47-3.53(m，2H)，4.40-4.48(m，1H)4.5(s，2H)，4.53-4.59(m，1H)，7.26-7.35(m，10H).

¹³C?NMR(mixture?of?rotamers)：174.4and173.7(C＝O)，142.05，141.68，138.14，138.10，128.06，127.93，127.91，127.85，127.53，127.25，127.19，127.11，127.05，126.51，126.16，75.49，74.72，72.42，69.73，69.64，57.86，56.72，33.39，32.79，31.64，28.95，28.80，26.56，21.67，21.36，15.06，13.94.

MS：C ₂₂H ₂₉NO ₃，356.3(MH ⁺).

The preparation of compound (14)

In the suspension of THF45ml, add Diisopropylamine 11.1ml (79.2mmol) to Lithium chloride (anhydrous) 9.0g (211.2mmol), the gained suspension is cooled to-78 ℃ in dry ice-propanone is bathed, drips n-Butyl Lithium (1.6M hexane solution) 45.8ml (73.22mmol) with sleeve pipe.The yellow suspension of gained stirs 10min down at 0 ℃, will be cooled to-78 ℃ with sleeve pipe in 10min then.The solution that ice-cold amine 13 12.5g (35.2mmol) is dissolved in dry THF 45ml adds, and washes with THF20ml again.Reaction mixture stirs 1h down at-78 ℃, stirs 15min down at 0 ℃ again, at room temperature stirs 5min at last, before being cooled to 0 ℃ again, adds methyl-iodide.Reaction mixture stirs 45min down at 0 ℃, adds saturated aqueous ammonium chloride 5ml stopped reaction.Obtain 14 12.25g (94%), a kind of thick liquid.

[α] ²⁰ _D＝92.22(c＝2.4，CHCl ₃)；

IR(Film，cm ^-1)：3391，2936，2864，1615，1455，1409，1103，1050，738，700.

¹H?NMR(mixture?of?rotamers)：δ0.96and1.01(d，J＝7Hz，3H，N-CH-CH3，rotamers)，1.16(d，J＝7Hz，3H)，1.39-1.79(m，4H)，2.59-2.68(m，1H)，2.73and2.91(s，3H，N-Me?rotamers)，3.39-3.51(m，2H)，4.29-4.45(m，1H)，4.45and4.48(s，2H，C ₆H ₅CH ₂，rotamers)，4.54-4.61(m，1H)，4.8-5.29(brs，1H，OH)，7.24-7.37(m，10H)；

¹³C?NMR(mixture?of?rotamers)：177.88and177.14(C＝O)，142.18，141.79.138.07，128.06，127.93，127.91，127.75，127.53，127.33，127.24，127.17，127.14，127.08，126.94.126.49，125.97，125.88，75.54，74.72，72.48，72.41，69.88，69.73，58.20，57.53，35.67，34.88，32.75.30.66，30.28，30.11，27.09，26.94，26.85，17.22，17.05，15.29，13.95.

MS：C ₂₃H ₃₁NO ₃，370.3(MH ⁺).

The preparation of compound (15)

Be dissolved in the solution of THF140ml to Diisopropylamine 19.1ml (136.5mmol) and n-Butyl Lithium (1.6M hexane solution) 79.2ml (126.75mmol), add a ammonia borane complex compound 4.5g (130mmol) down at 0 ℃, the gained suspension stirs 15min down at 0 ℃, be warming up to room temperature, stir 15min.Reaction mixture is cooled to 0 ℃ again, adds the solution (then washing away with 20ml THF) that amine 14 12g (32.5mmol) are dissolved in THF85ml with sleeve pipe.Reaction mixture rises to room temperature, stirs 16h, is cooled to 0 ℃, adds 3N aqueous hydrochloric acid 330ml stopped reaction.Thereafter, stir 30min down at 0 ℃, reaction mixture extracted with diethyl ether (3 * 160ml), the organic extract liquid that merges is used 3N aqueous hydrochloric acid 60ml successively, 2N aqueous sodium hydroxide solution 60ml and salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure, residue stirs 1h with 1N aqueous sodium hydroxide solution 65ml, with extracted with diethyl ether (3 * 150ml), the organic phase water and the salt water washing that merge, dried over sodium sulfate is after steaming desolventizes, crude product alcohol purification by flash chromatography, wash-out: 2: 8 ethyl acetate: hexane obtains 15 5.1g (75%), a kind of colourless liquid.

IR(Film，cm ^-1)：3391，2936，2870，1496，1455，1361，1205，1099，1029，737，698；

¹H?NMR：δ0.93(d，J＝6.7Hz，3H)，1.1-1.3(m，1H)，1.45-1.78(m，4H)，3.41-3.51(m，4H)，4.51(s，2H)，7.26-7.35(m，5H)；

¹³C?NMR：d138.09，128.01(2C)，127.33(2C)，127.20，72.54，70.39，67.21，35.16，29.25，26.74，16.3.

MS：C ₁₃H ₂₀O ₂，209.2(MH ⁺).

The preparation of compound (16)

Be dissolved in to the oxalyl chloride 2.44ml (28mmol) that is cooled to-78 ℃ and add dry dimethyl sulfoxide (DMSO) 3.98ml (56mmol) in the solution of methylene dichloride 60ml, after the 5min, add the solution that pure 15 4.2g (20mmol) are dissolved in methylene dichloride 10ml with sleeve pipe, the white suspension of gained stirs 30min down at-78 ℃, add triethylamine 12.28ml (88mmol) then, the 20ml that then adds methylene chloride again is to the dense thick suspension that still can stir.After-30 ℃ were stirred 40min down, reaction mixture diluted with pentane 300ml.(2 * 100ml), (2 * 100ml) wash water organic phase again with the washing of 1M aqueous solution of sodium bisulfite.The organic layer anhydrous sodium sulfate drying that merges, removal of solvent under reduced pressure (bathing 30 ℃～35 ℃ of temperature).Purification by flash chromatography, wash-out: 2: 8 ethyl acetate: hexane obtains pure 16 3.44g (84%).

¹H?NMR：δ1.10(d，J＝6.7Hz，3H)，1.41-1.52(m，1H)，1.61-1.71(m，2H)，1.73-1.88(m，1H)，2.04-2.39(m，1H)，3.48(t，J＝6Hz，2H)，4.52(s，2H)，7.26-7.38(m，5H)，9.61(d，J＝4Hz，1H，CHO)；

¹³C?NMR：d204.83，138.09，128.27(2C)，127.50(2C)，127.46，72.82，69.82，45.93，27.04(2C)，13.24.

The preparation of compound (17)

Under 0 ℃, be dissolved in the solution of methylene dichloride 48ml to (S)-4-benzyl-3-propionyl-2-oxazolidone 7.78g (33.4mmol), in 50min, add boron trifluoride ether complex (1.0M dichloromethane solution) 36.74ml (36.74mmol).In adition process, solution transfers to orange.Behind reinforced the end, add triethylamine 5.6ml (40.08mmol) in 10min, the faint yellow reaction mixture of gained stirs 45min down at 0 ℃, is cooled to-78 ℃ again, add a aldehyde 16 3.44g (16.7mmol) then, (then washing away with the 2ml methylene dichloride).Reaction mixture stirs 30min down at-78 ℃, then at 0 ℃ of following restir 2h.Add phosphoric acid buffer (pH7.0) 72ml stopped reaction.Slowly add 30% hydrogen peroxide (H ₂O ₂) 7.2ml, reaction mixture stirs 30min down at 5 ℃, tells water, and (2 * 100ml), the organic phase of merging washes with water 1 time, with salt water washing 1 time with dichloromethane extraction.By anhydrous sodium sulfate drying, concentrating under reduced pressure.The crude product purification by flash chromatography, wash-out: 2: 8 ethyl acetate: hexane, then 3: 7 ethyl acetate: hexane.Obtain aldol 1714g, (95%) 96: 4 non-enantiomer mixtures.

¹H?NMR(major?diastereomer)：δ0.89(d，J＝6.8Hz，3H)，1.23(d，J＝7Hz，3H)，1.49-1.86(m，5H)，2.77(dd，J＝13.4，9.5Hz，1H)，2.99(brs，1H)，3.25(dd，J＝13.3，3.2Hz，1H)，3.43-3.54(m，2H)，3.62(dd，J＝9，2Hz，1H)，3.95(dd，J＝9，3.2Hz，1H)，4.15-4.27(m，2H)，4.5(s，2H)，4.64-4.74(m，1H)，7.21-7.53(m，10H)；

¹³C?NMR(major?diastereomer)：d177.83，152.82，138.55，135.00，129.37(2C)，128.90(2C)，128.28(2C)，127.59(2C)，127.42，127.36，75.03，72.81，70.78，66.08，55.10，39.46，37.69，35.46，29.11，26.80，15.36，9.63.

The preparation of compound (18)

Under 0 ℃, to N, O-dimethyl hydroxylamine hydrochloride 9.15g (93.8mmol) is dissolved in and adds trimethyl aluminium (2.0M hexane solution) 48ml (96mmol) when reinforced (have gas to emit at first) in the solution of dry THF 55ml with sleeve pipe.The clear solution of gained stirs 45min under room temperature, it is cooled to-5 ℃, adds the solution that aldol 17 13.73g (31.24mmol) are dissolved in THF55ml with sleeve pipe.Reaction mixture transfers muddiness to, becomes limpid behind 15～20min again.Reaction mixture rises to room temperature gradually in 16h, reaction mixture imports Seignette salt (Rochelle salt) saturated aqueous solution 150ml through sleeve pipe, stirs 1h.Tell organic layer, and the water dichloromethane extraction (3 * 100ml), the salt water washing of the organic phase of merging, anhydrous sodium sulfate drying, concentrating under reduced pressure.The crude product purification by flash chromatography, wash-out: 1: 1 t-butyl methyl ether (t-butyl methyl ether, [1634-04-4]): hexane.Obtain pure diastereomer 18 8.0g (80%), a kind of toughening oil.

[α] ²⁰ _D＝-11.97(c＝1.57，CHCl ₃)；

IR(Film，cm ^-1)：3460，2937，2872，1651，1456，1386，1101，993，739，699；

¹HNMR：δ0.86(d，J＝6.8Hz，3H)，1.14(d，J＝6.3Hz，3H)，1.19-1.28(m，1H)，1.49-1.64(m，2H)，1.72-1.87(m，2H)，3.08-3.10(m，1H)，3.19(s，3H)，3.43-3.53(m，3H)，3.69(s，3H)，3.99(s，1H)，4.50(s，2H)，7.24-7.34(m，5H)；

¹³C?NMR：d178.44，138.56，128.17(2C)，127.49(2C)，127.28，75.21，72.22，70.85，61.37，35.45，35.06，31.80，28.79，26.84，15.32，9.61.MS：C ₁₈H ₂₉NO ₄，324.2(MH ⁺).

The preparation of compound (19)

Under 0 ℃, be dissolved in to amine 188.0g (25mmol) in the solution of methylene dichloride 60ml and add 2,6-lutidine 10.2ml (87.5mmol) then adds tertiary butyl dimethyl silyl triflate 12ml (52.25mmol), and reaction mixture stirs 30min down at 0 ℃.Add saturated sodium bicarbonate aqueous solution 100ml stopped reaction.Tell organic layer, and the water layer dichloromethane extraction (2 * 100ml), the organic layer water of merging and salt water washing, anhydrous sodium sulfate drying, concentrating under reduced pressure.The crude product purification by flash chromatography, wash-out: 2: 8 ethyl acetate: hexane.After steaming solvent, the product that obtains is dissolved in methylene dichloride 45ml and hexane 150ml, concentrating under reduced pressure, and high vacuum dry 16h obtains silicon ether 19 10.5g (96%), a kind of colourless liquid.

IR(Film，cm ^-1)：2935，2857，1652，1463，1385，1257，1053，997，837，775，698；[0]

¹HNMR：δ0.06(s，3H)，0.58(s，3H)，0.85(s，9H)，0.88(d，J＝6.8Hz，3H)，1.07(d，J＝6.9Hz，3H)，0.91-1.08(m，1H)，1.35-1.67(m，4H)，3.06(s，3H)，3.02-3.06(m，1H)，3.37(5，J＝6.5Hz，2H)，3.57(s，3H)，3.81(dd，J＝8.2，2Hz，1H)，4.42(s，2H)，7.19-7.28(m，5H)；

¹³C?NMR：176.81，138.35，127.92(2C)，127.19(2C)，127.05，76.33，72.45，70.47，60.97，38.43，37.76，31.90，27.77，27.59，25.79(3C)，18.02，16.00，15.26，-4.21，-4.28.

MS：C ₂₄H ₄₃NO ₄Si，438.4(MH ⁺).

The preparation of compound (20)

Be dissolved in the solution of THF90ml to silylated acid amides 19 10.4g (24mmol) that are cooled to-78 ℃, in 30min, add diisobutyl aluminium hydride (1.0M toluene solution) 50ml (50mmol).Reaction mixture stirs 30min down at-78 ℃, temperature is risen to-50 ℃ afterwards in 30min.Add methyl alcohol 1.5ml (37mmol) down at-78 ℃, so that excessive diisobutyl aluminium hydride stopped reaction.Then, reaction mixture stirs 30min, and reaction mixture imports among the saturated soluble tartrate sodium water solution 250ml through sleeve pipe, adds methylene dichloride 100ml, and mixed solution at room temperature stirs 30min, tells organic phase, water dichloromethane extraction (2 * 100ml).The organic phase salt water washing that merges, dried over sodium sulfate, concentrating under reduced pressure (bathing 30～35 ℃ of temperature).Crude product aldehyde is at short silicagel column purifying, wash-out: 2: 8 ethyl acetate: hexane.Obtain aldehyde 20 8.2g (91%).

¹HNMR：δ0.0(s，3H)，0.06(s，3H)，0.87(s，9H)，0.92(d，J＝7Hz，3H)，1.1(d.J＝7Hz，3H)，1.09-1.16(m，1H)，1.46-1.78(m，4H)，2.36-2.52(m，1H)，3.45(t，J＝6.5Hz，2H)，4.00(dd，J＝5.5，3.6Hz，1H)，4.5(s，2H)，7.26-7.38(m，5H)，9.72(d，J＝1Hz，1H)；

¹³C?NMR：205.06，138.47，128.26(2C)，127.55(2C)，127.42，74.80，72.87，70.46，49.80，37.94，29.02，27.66，25.85(3C)，18.16，15.79，8.59，-4.25(2C).

The preparation of compound (21)

Prenyl magnesium chloride intermediate preparation: 1-chloro-3-methyl-2-butene 5.65ml (50mmol) and magnesium powder 3.65g (150mmol) react in THF64ml.

Be dissolved in to aldehyde 20 8.0g (21.34mmol) and drip prenyl magnesium chloride (0.78M) 45ml (35mmol) in cold (0 ℃) solution of THF40ml, reaction mixture at room temperature stirs 1h, adds saturated aqueous ammonium chloride 40ml stopped reaction.Remove solvent under reduced pressure, and the residue dichloromethane extraction (2 * 100ml), the salt water washing of the organic phase of merging, dried over sodium sulfate, concentrating under reduced pressure, purification by flash chromatography, wash-out: 2: 98 ethyl acetate: hexane, then, 5: 95 ethyl acetate: hexane.Obtain pure 9.0g (94%), a kind of non-enantiomer mixture.

Be dissolved in methylene dichloride to pure 9.0g (20mmol) non-enantiomer mixture: add Powdered in the solution of acetonitrile (4: 1) 50ml

Molecular sieve 10g and anhydrous N-methylmorpholine oxide compound 4.7g (40mmol) then add four n-propyls and cross the sour ammonium 705mg of ruthenium (VII) (2mmol), and the dark-coloured suspension of gained at room temperature stirs 2h, removes solvent then under reduced pressure.The residue purification by flash chromatography, the pillar top adds a small amount of diatomite.Wash-out: 2: 98 t-butyl methyl ether: hexane, then, 5: 95 ethyl acetate: hexane.Obtain ketone 21 6.8g (76%), a kind of weak yellow liquid.

IR(Film，cm ^-1)：2932，2857，1703，1634，1463，1362，1256，1114，987，877，837，775，735，697；

¹H?NMR：δ0.0(s，6H)，0.84(s，9H)，0.85(d，J＝5.6Hz，3H)，0.97(d，J＝7Hz，3H)，1.01-1.11(m，1H)，1.14(s，3H)，1.17(s，3H)，1.2-1.43(m，3H)，1.58-1.68(m，1H)，3.08(quintet，J＝7Hz，1H)，3.38(t，J＝6.4Hz，2H)，3.75(dd，J＝8，2Hz，1H)，4.44(s，2H)，5.07(dd，2H)，5.87(dd，J＝17，11Hz，1H)，7.19-7.29(m，5H)；

¹³C?NMR：d216.15，142.31，138.56，128.21(2C)，127.44(2C)，127.35，114.21，76.99，72.75，70.76，51.35，44.36，38.63，27.95，27.26，26.13(3C)，23.95，23.72，18.39，17.26，16.67，-3.79，-3.82.

The preparation of compound (22)

Be dissolved in to ketone 21 6.8g (15.22mmol) in the mixing solutions of THF24ml and trimethyl carbinol 12ml, add water 6ml, add N-methylmorpholine oxide compound 2.2g (18.78mmol) and perosmic anhydride 2.5wt% t-butanol solution 8ml (0.787mmol) then.The yellow solution of gained at room temperature stirs 16h.Add S-WAT 8.35g, add water 150ml stopped reaction then.The dark-coloured reaction mixture that obtains at room temperature stirs 45min.Tell organic layer, (2 * 100ml), the organic phase of merging washes with water 1 time water, with salt water washing 1 time, dried over sodium sulfate, concentrating under reduced pressure with ethyl acetate extraction.The residue purification by flash chromatography, wash-out: 2: 8 ethyl acetate: hexane, then, 1: 1 ethyl acetate: hexane.The glycol that separates is dense thick liquid, and trimethyl carbinol slight pollution is arranged, and need not to be further purified namely to can be used for next step reaction.Be dissolved in to glycol and add a sodium periodate 5.0g (23.23mmol) in the solution of THF75ml, add water 75ml then, the colourless soup compound of gained at room temperature stirs 6h.Reaction mixture is told organic layer with methylene dichloride 100ml dilution, water dichloromethane extraction (2 * 100ml) organic layer water and the salt water washings that merge, dried over sodium sulfate, concentrating under reduced pressure.The residue purification by flash chromatography, wash-out: 2: 8 ethyl acetate: hexane obtains aldehyde 22 6.29g (two steps 92%).

¹H?NMR：δ0.05(s，3H)，0.06(s，3H)，0.89(s，9H)，0.91(d，J＝7Hz，3H)，1.02(d，J＝7.3Hz，3H)，1.01-1.25(m，1H)，1.32(s，3H)，1.33(s，3H)，1.25-1.53(m，2H)，1.65-1.74(m，2H)，3.05(quintet，J＝7Hz，1H)，3.45(t，J＝7.6Hz，2H)，3.86(dd，J＝7.6，2.6Hz，1H)，4.49(s，2H)，7.22-7.35(m，5H)，9.59(s，1H)；

[01234] ¹³C?NMR：d212.29，200.54，138.53，128.19(2C)，127.46(2C)，127.34，76.35，72.76，70.49，60.97，45.31，38.96，27.88(2C)，26.03(3C)，19.83，19.72，18.31，16.61，15.38，-3.97(2C).

The preparation of compound (23)

In-78 ℃ of solution that are dissolved in ether 20ml to freshly prepd LDA (0.5M diethyl ether solution) 18ml (9.0mmol), add tebutate 1.16ml (8.61mmol), stir 50min after, drip CpTiCl (OPh) by syringe pump through 65min ₂(self-control) (0.1M diethyl ether solution) 100ml (10.0mmol), stir 20min, reaction mixture is heated to-30 ℃, stir 50min and be cooled to-78 ℃ again, drip the solution that aldehyde 22 2.42g (5.75mmol) are dissolved in ether 9ml through 10min, and stir the gained mixture down at-78 ℃, behind the stirring 2h, make reaction stop and under room temperature, stir 2h with THF (5M HO) aqueous solution 37ml, after adding water 40ml, with mixture restir 1h, by diatomite (ether cleaning), the formed throw out of filtering, and water 40ml wash filtrate, and the water layer extracted with diethyl ether (2 * 100ml), with the organic layer salt water washing that merges, dried over sodium sulfate, concentrating under reduced pressure, by purification by flash chromatography, wash-out: 1: 10 ethyl acetate: hexane, obtain pure 23 2.65g (86%), a kind of light yellow oil.

[α] ²⁰ _D＝-41.0(c＝0.4，CHCl ₃)；

IR(Film，cm ^-1)：3502，2959，2875，1731，1683，1456，1366，1154，1098，996，739；

¹H?NMR(400MHz，CDCl3))：δ(m，6H)0.96(d，J＝7.9Hz，9H)，0.97(d，J＝6.8Hz.3H)，1.05(d，J＝6.8Hz，3H)，1.11(s，3H)，1.26-1.45(m，4H)，1.58-1.90(m，1H)，2.21(dd，J＝6.7，17.0Hz，1H)，2.36(dd，J＝6.7，17.0Hz，1H)，3.24-3.29(m，1H)，3.44-3.52(m，2H)，3.67(dd，J＝3.9，and8.9Hz，1H)，4.36(dd，J＝3.5and6.5Hz，1H)，4.50(d，J＝12.0Hz，1H)，7.32-7.36(m，5H)；

¹³C?NMR(100MHz，CDCl3)δ5.0，6.9，9.7，13.9，20.2，21.8，28.0，36，3，40.8，41.5，53.7.72.5，72.9，73.2，73，6，80.7，127.4，127.5，128.2，138，6，171.0，221.4；

LRMS(ESI)C ₃₂H ₅₈O ₆SiCl ₃Na[M+Na ⁺].

The preparation of compound (24)

Under 0 ℃, add TBSCl3.3ml (19.8mmol) to pure 23 10.2g (8.9mmol) with the mixture of imidazoles 2.70g (39.7mmol) in DMF25ml, and under room temperature, mixture is stirred 2h, use saturated sodium bicarbonate aqueous solution 50ml stopped reaction then, with hexane extraction (500ml+120ml * 2), the organic extract that merges is water (30ml * 2) successively. salt solution 30m] and washing, dried over sodium sulfate, concentrating under reduced pressure, by the fast silica gel chromatogram purifying, wash-out: l: 40 ethyl acetate: hexane.Obtain 24 12.1g (98%), a kind of water white oil.

IR(Film，cm ^-1)：3445，2955，2858，1745，1695，1473，1373，1257，1090，989，837，776，670；

¹H?NMR：δ0.05(s，3H)，0.00(s，6H)，0.04(s，3H)，0.81(s，9H)，0.84(s，9H)，0.87(d，J＝6.8Hz，3H)，0.99(d，J＝6.9Hz，3H)，1.03(s，3H)，1.16(s，3H)，1.19-1.66(m，6H)，2.22(dd，J＝16，7.1Hz，1H)，2.36(dd，J＝16，3Hz，1H)，3.09(quintet，J＝7Hz，1H)，3.57(t，J＝6.6Hz，2H)，3.61(s，2H)，3.73(dd，J＝7.3，2Hz，1H)，4.34(dd，J＝7，3Hz，1H)，0.91(s，9H，OSiC(CH3)3)，0.17，0.14(2s，2×3H；OSi(CH3)2)；

¹³C?NMR：d218.53，172.91，77.95，73.94，63.61，53.89，52.03，45.51，40.51，m38.87，31.35，27.19，26.58(3C)，26.34(3C)，24.08，19.38，18.86，18.56，18.04，16.10，-3.29，-3.39，-4.12，-4.24.

The preparation of compound (25)

In being dissolved in stirring solution among the THF67ml, 24 4.37g (6.72mmol) add Pd/C10%wt437mg, at H ₂Atmosphere (annotate: air bag is kept) stirs this mixture down.After stirring 2.2h, filter this mixture with Celite pad, wash Celite pad with THF120ml.Concentrating under reduced pressure, by the fast silica gel chromatogram purifying, wash-out: 1: 30 to 1: 10 ethyl acetate: hexane.Obtain pure 25 3.35g (94%), a kind of water white oil.

¹HNMR：δ0.04(s，3H)，0.01(s，3H)，0.00(s，6H)，0.78(s，9H)，0.83(s，9H)，0.87(d，J＝6.8Hz，3H)，0.98(d，J＝7Hz，3H)，1.01-1.1(m，4H)，1.14(s，3H)，1.17-1.65(m，5H)，2.24(dd，J＝16，6.7Hz，1H)，2.33(dd，J＝16，3.8Hz，1H)，3.07(quintet，J＝7Hz，1H)，3.55(t，J＝6.6Hz，2H)，3.61(s，2H)，3.75(dd，J＝7.3Hz，1.8Hz，1H)，4.48(dd，J＝6.7Hz，3.8Hz，1H)，0.91(s，9H，OSiC(CH3)3)，0.17，0.14(2s，2×3H；OSi(CH3)2).

The preparation of compound (26, fragment 2)

Be dissolved in to pure 25 4.2g (7.68mmol) in the solution of dry THF12ml and pyridine 4ml; add 2-nitrophenyl seleno cyanate 4.36g (19.2mmol); add tributylphosphine 4.8ml (19.3mmol) then; the dark red suspension that obtains lucifuge under room temperature, argon shield stirs 16h; removal of solvent under reduced pressure; residue is by fast silica gel chromatogram purifying, wash-out: 5: 95 ethyl acetate: hexane to 1: 9 ethyl acetate: hexane.Obtain selenide 5.4g (96%), the dense thick liquid of a kind of yellow.

Under-15 ℃, be dissolved in to selenide 5.4g (7.4mmol) and add a m-chlorobenzoic acid (57%～80%) 2.7g in the solution of methylene dichloride 15ml, reaction mixture becomes red suspension, stir 30min down at-15 ℃, add Diisopropylamine 2.2ml (15.7mmol), the dark red solution of gained rises to room temperature, stir 30min, add water, add saturated sodium bicarbonate aqueous solution then, reaction mixture ethyl acetate extraction (3 * 100ml).The organic phase that merges is used saturated sodium bicarbonate aqueous solution, salt water washing, dried over sodium sulfate, concentrating under reduced pressure successively.Residue is by fast silica gel chromatogram purifying, wash-out: 2: 98 ethyl acetate: hexane to 5: 95 ethyl acetate: hexane.Obtain alkene 26 (fragment 2) 2.6g (67%), a kind of yellow oil.

IR(Film，cm ^-1)：2956，2858，1747，1695，1641，1472，1297，1256，1091，989，837，776，668；

¹HNMR：δ0.01(s，3H)，0.06(s，3H)，0.07(s，3H)，0.09(s，3H)，0.87(s，9H)，0.89(d，J＝6Hz，3H)，0.91(s，9H)，1.05(d，J＝7Hz，3H)，1.08(s，3H)，1.23(s，3H)，1.35-1.45(m，1H)，1.79-1.90(m，1H)，2.27(dd?overlapped?with?a?multiplet，J＝16，7Hz，2H)，2.42(dd，J＝16，3Hz，1H)，3.16(quintet，J＝7Hz，1H)，3.67(s，3H)，3.82(dd，J＝8，1.8Hz，1H)，4.41(dd，J＝7，3.2Hz，1H)，4.97-5.03(m，2H)，5.66-5.79(m，1H)；

¹³C?NMR：δ217.98，172.37，137.76，115.68，77.65，73.66，53.50，51.59，45.62.40.19，38.00，35.16，26.24(6C)，25.96(3C)，23.68，19.11，18.54，18.18，18.00，15.72，-3.53.-3.66，-4.51，-4.63.

Synthesizing of embodiment 3 ipsapirones

The synthetic route of ipsapirone

The preparation of compound (II)

Be dissolved in interior 9-boron dicyclo [3.3.1] nonane dipolymer (9-BBN dimmer) 2.10g (8.63mmol) of adding of solution of THF25ml to 26 (fragment 2) 5.80g (11.22mmol).The gained mixed solution is after stirring 1h under 25 ℃, and it is complete to consuming that TLC detects starting raw material Fragment2.12 (fragment 1) 3.22g (8.63mmol) are housed, [1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II) methylene dichloride adducts (dppf) PdCl in independent separately flask ₂CH ₂Cl ₂) 0.705g (0.862mmol), triphenylarsine 0.264g (0.862mmol) and cesium carbonate 4.21g (12.94mmol) are dissolved in the DMF30ml of the degassing.Add water 5ml to borine solution, continue to stir 10min, to end excessive 9-BBN-H.Then, alkyl borane solution is joined rapidly in the solution that contains Fragment1 that vigorous stirring.After the 2h, reaction mixture is with ethyl acetate 300ml dilution, water (1 * 250ml), (dried over sodium sulfate is passed through in 1 * 250ml) washing to salt solution, filter concentrating under reduced pressure, silica gel chromatography purifying, wash-out: 10%EtOAc/hexanes obtains II4.56g (70%), a kind of yellow oil.

[α] ²⁰ _D＝-13.8(c＝1.0，CHCl ₃)；

Rf＝0.38in20％EtOAc/hexanes。

The preparation of compound (III)

The solution that is dissolved in THF100ml to II4.10g (5.36mmol) adds triphenylphosphine 2.81g (10.71mmol), and solution is heated to 40 ℃, stirs 19h, adds water 2ml, is heated to 65 ℃ then, stirs 4h.Add silica gel 70g, remove solvent under reduced pressure, the silica gel chromatography purifying, wash-out: 1.5%MeOH/chloroform containing0.5%triethylamine obtains a kind of reduction amine 3.9g (98%), [α] ²⁰ _D=-4.4 (c=1.0, CHCl ₃); Rf=0.38in10% methyl alcohol/chloroform (containing 1% triethylamine).

The amine 3.30g (4.48mmol) that upwards goes on foot gained is dissolved in the solution adding tert-Butyl dicarbonate 1.37g (6.27mmol) of acetonitrile 300ml, add triethylamine 0.91g (8.57mmol) then,. reaction mixture stirs 16h under room temperature, solution dilutes with ethyl acetate 100ml, with 1N hydrochloric acid (1 * 100ml), saturated sodium bicarbonate aqueous solution (1 * 100ml) and salt solution (1 * 100ml) washing, pass through dried over mgso, filter, concentrating under reduced pressure, the silica gel chromatography purifying, washing: 10%EtOAc/hexanes. obtains III2.66g (70%), a kind of platinum sponge shape.

[α] ²⁰ _D＝-14.5(c＝1.0，CHCl ₃)；

Rf＝0.60in40％EtOAc/hexanes。

The preparation of compound (IV)

The solution that is dissolved in acetone 9ml to III0.309g (0.363mmol) adds tosic acid 0.083g (0.436mmol).Stir 22h under the room temperature, reaction mixture adds the saturated sodium bicarbonate aqueous solution neutralization, with ethyl acetate extraction (3 * 30ml), the organic layer that merges filters concentrating under reduced pressure by dried over mgso, the silica gel chromatography purifying, wash-out: 15%EtOAc/hexanes obtains beta-ketoester IV0.25g (82%), a kind of platinum sponge shape thing.

[α] ²⁰ _D＝-36.8(c＝1.0，CHCl ₃)；

Rf＝0.28in10％EtOAc/toluene。

The preparation of compound (V)

Under 25 ℃, diketone IV1.234g (1.48mmol) is dissolved in the methanol solution 24.6ml (2.95mmol) that contains 0.12N hydrochloric acid, this solution sprays 30min with argon gas then, add 1, two (2,4,6-trimethylphenyl)-2-(imidazolidine subunit) (dichlorobenzene methylene radical) (tricyclohexyl phosphine) the ruthenium 0.15g (0.089mmol) of 3-, reaction mixture changes (miniature) hydrogenation high pressure reaction assembly over to, charges into H in the retort ₂10min is forced into 1250psi then and (annotates: 1250psi=87.9kg/cm ²).Behind the reaction 18h, normal pressure is injected in reaction under 25 ℃.Pour among the saturated sodium bicarbonate aqueous solution 60ml, (3 * 100ml), the organic layer of merging passes through dried over mgso with ethyl acetate extraction, filter concentrating under reduced pressure, silica gel chromatography purifying, wash-out: 20%EtOAc/hexanes obtains hydroxy ester V0.955g (78%), a kind of platinum sponge shape thing.

[α] ²⁰ _D＝-33.5(c＝1.0，CHCl ₃)；

Rf＝0.20in20％EtOAc/toluene。

The preparation of compound (VI)

V0.738g (0.880mmol) is dissolved in methylene dichloride 20ml, adds trifluoroacetic acid 10ml, and mixed solution stirs 2h under room temperature, concentrating under reduced pressure then, and the gained crude product need not purifying can enter next reactions steps.

The crude mixture that the last step was obtained is dissolved in DMF10ml, again with methylene dichloride 500ml dilution.Add N-hydroxyl-7-azepine benzotriazole then, (HOAt) 0.359g (2.64mmol) adds N then, and N-diisopropylethylamine 1.02g (7.92mmol) adds HATU0.359g (2.64mmol) at last.The gained mixed solution stirs 16h down at 25 ℃, and the reaction mixture water (filter by dried over mgso, and concentrating under reduced pressure is dissolved in HOAc/THF/H with crude mixture through 30min then by 1 * 100ml washing, organic layer ₂O (3: 1: 1) 30ml; the reaction mixture concentrating under reduced pressure; transfer to neutrality with saturated sodium bicarbonate aqueous solution, (3 * 100ml), the organic layer of merging passes through dried over sodium sulfate with ethyl acetate extraction; filter; concentrating under reduced pressure, silica gel chromatography purifying, wash-out: 45%EtOAc/hexanes; obtain azadEpioB (26) 0.479g (79%) of Troc-protection and C-15-epi-azadEpoB (the asymmetric dihydroxy of the from88%ee) 0.065g (11%) of Troc-protection, a kind of platinum sponge thing.It is dissolved in the high-activity nano zinc powder that adds a point of scraping in the solution of THF/HOAc (1: 3) 6ml, and reaction mixture is used ultrasonication 2h down at 25 ℃, and solution removes by filter zinc powder.Then, concentrating under reduced pressure, residue are dissolved in ethyl acetate 20ml, neutralize with saturated sodium bicarbonate aqueous solution 10ml, (2 * 20ml), the organic layer of merging filters by dried over mgso water layer with ethyl acetate extraction, concentrating under reduced pressure, the silica gel chromatography purifying, wash-out: 60%EtOAc/hexanes obtains (VI, aza-dEpoD) 0.025g (88%), a kind of platinum sponge shape thing.

The preparation of compound (I, ipsapirone)

VI0.025g (0.051mmol) solution dichloromethane 2ml is cooled to-78 ℃, slowly adds dimethyl ketone peroxide (DMDO) 0.6M (0.11mmol), then reaction mixture is warming up to-50 ℃, stirs 1h.Add dimethyl thioether 0.1ml down at-50 ℃, rise to room temperature, the silica gel chromatography purifying, wash-out: 80%EtOAc/hexanes obtains complete synthesis (I, aza-EpoB, ipsapirone) 0.018g (69%), a kind of platinum sponge shape thing.

[α] ²⁰ _D＝-34.1(c＝1.0，CHCl ₃)；

Rf＝0.4in100％EtOAc；

IR(neat)3319，2931，1661，1643，1536，1453，1372，1185，753cm ^-1；

¹H?NMR(500MHz，CDCl ₃)δ6.97(s，1H)，6.83(d，J＝8.0Hz，1H)，6.55(s，1H)，4.66-4.64(m，1H)，4.25(d，J＝6.2Hz，1H)，4.03-4.01(m，1H)，3.83-3.81(m，1H)，3.38-3.33(m，1H)，2.81(dd，J＝7.2，6.4Hz，1H)，2.70(s，3H)，2.62(brs，OH，1H)，2.43(dd，J＝14.7，9.3Hz，1H)，2.32(dd，J＝14.7，2.9Hz，1H)，2.13(s，3H)，2.04-1.97(m，4H)，1.69-1.38(m，5H)，1.34(s，3H)，1.27(s，3H)，1.17(d，J＝6.9Hz，3H)，1.12(s，3H)，0.99(d，J＝7.0Hz，3H)；

¹³C?NMR(125MHz，CDCl ₃)δ221.0，170.6，165.0，152.6，137.8，119.4，116.2，75.0，74.1，61.4，61.1，54.7，52.4，43.9，40.4，38.0，31.9，31.8，30.7，23.9，23.1，21.7，21.6，19.4，17.3.17.1，14.5；

LRMS(+electrospray)529.0[M+Na] ⁺，507.0[M+H] ⁺.

HRMS?cald?for?C ₂₇H ₄₂N ₂O ₅S，506.2814，found506.2796。

Claims

1. one kind suc as formula the ipsapirone of I or the total synthesis method of its salt,

Wherein:

R1 represents NH,

R4 represents hydrogen or low alkyl group,

R6 is hydrogen, and

R7 is hydrogen,

Z is O,

Condition is:

2. the ipsapirone of formula Ia or Ib or its salt,

Wherein:

R1 represents NH,

R4 represents hydrogen or low alkyl group,

R6 is hydrogen, and

R7 is hydrogen,

Z is O,

Condition is:

3. according to the formula I of claim 1 or according to the formula Ia of claim 2 or ipsapirone or its salt of Ib, wherein:

R1 represents NH,

R4 represents hydrogen or low alkyl group,

R6 is hydrogen, and

R7 is hydrogen,

Z is O,

Condition is:

4. according to the formula I of claim 1 or according to the formula Ia of claim 2 or ipsapirone or its salt of Ib, wherein:

R1 represents NH,

R3 is thiazolyl, oxazolyl, pyridyl, benzothiazolyl, and they do not replace separately or are substituted,

R4 represents hydrogen or low alkyl group,

R6 is hydrogen, and

R7 is hydrogen,

Z is O,

Condition is:

5. according to the formula I of claim 1 or according to the formula Ia of claim 2 or ipsapirone or its salt of Ib, wherein:

R1 represents NH,

R2 is hydrogen or low alkyl group,

R3 is 2-methyl-thiazolyl, 2-ethyl-thiazolyl, 2-methylthio group-thiazolyl, 2-amino methyl-thiazolyl, 2-dimethylamino-thiazolyl, 2-methyl fluoride-thiazolyl, 2-methyl-oxazolyls, 3-methyl-pyridyl, 2-methyl-benzothiazolyl,

R4 represents hydrogen or low alkyl group,

R6 and R7 are hydrogen, and

Z is O,

Condition is: when R2 was 2-methyl-thiazolyl, Z was that O and R2 represent low alkyl group.

6. according to the formula I of claim 1 or according to the formula Ia of claim 2 or ipsapirone or its salt of Ib, wherein:

A represents NH,

R2 is hydrogen or low alkyl group,

R4 represents methyl,

R6 and R7 are hydrogen,

Z is O,

Condition is: when R3 was 2-methyl-thiazolyl, Z was that O and R2 represent low alkyl group.

7. the method for the ipsapirone of a preparation formula I,

Wherein:

R1 represents NH,

R4 represents hydrogen or low alkyl group,

R6 is hydrogen, and

R7 is hydrogen,

Z is O,

Wherein in the first step, use formula II,

Wherein R1, R2 and R3 are similar and different protecting groups.

Obtain the aldol of formula IV,

In the 3rd step, the carboxylic acid that makes formula IV with can not cause removing the reagent react of removing protecting group R4 under the condition of protecting group R5 and R6, obtain the carboxylic acid of formula IV; wherein R1, R2, R3 and Z have as above to the given implication of formula I compound; R4 is hydrogen, and R5 is that H or R5 and R6 are protecting groups

In the 4th step, the carboxylic acid of formula IV is carried out the macrolide reaction, obtain the esperamicin of formula I, wherein R1, R2, R3 and Z have as above the given implication of formula I compound, and R1 is NH, and R5 is that H or R5 and R6 are protecting groups,